Scientists identify mechanism in immune cells that may explain why organs age

Stanford Medicine researchers have found that a single receptor on immune cells governs how well the body clears out worn-out cells – blocking it kept mouse brains, hearts and other organs measurably younger

While ageing progresses at different rates no one can escape it. A study of mice and human cells by a research team from Stanford Medicine, California, USA, has traced much of this decline to a single immune cell type’s diminishing ability to clear another.

Tissue-resident macrophages appear to act as central coordinators of age-related organ decline. Blocking one receptor on these cells preserved youthfulness in mice across multiple organs, including the brain, heart, skeletal muscle, liver, spleen, bone marrow, kidney and colon. The receptor binds a hormone linked to inflammation and pain.

Selectively disabling this receptor only on tissue-resident macrophages prevented several disorders driven by chronic inflammation, including frailty, excess fat accumulation and heart problems. It also substantially slowed cognitive decline, said Dr. Katrin Andreasson, professor of neurology and neurological sciences at Stanford Medicine and is senior author of the study.

“We’ve been trying to work out why we age. Now we know at least one significant reason for it,” she said.

Neutrophils, the most abundant white blood cells, are the body’s first responders against pathogens, releasing toxic compounds and self-destructing to trap invaders. They are short-lived, rarely surviving for more than a day and most end up in the liver, spleen and bone marrow awaiting disposal by other immune cells.

This process of clearance is critical. In aged animals, most neutrophils that never meet a pathogen become senescent, damaging neighbouring cells by leaking toxic chemicals. Neutrophil counts rise with age, with senescent cells forming a growing share.

“Senescent neutrophils are [therefore], in effect, killing our tissues,” Andreasson said.

Clearing these dying cells falls to macrophages, which patrol tissue, engulf pathogens and repair damage caused by the body’s senescent cells. Tissue-resident macrophages settle in organs during foetal development and remain for life, clearing roughly 100 billion neutrophils daily that begin showing senescence within eight to twelve hours. But these macrophages age and become increasingly prone to spreading age-related inflammation.

Immune cells produce hormones called prostaglandins. One example is prostaglandin E2 (PGE2) has different effects depending on which receptor a cell carries. One receptor – EP2 – is strongly pro-inflammatory and abundant on tissue-resident macrophages. Ageing increases both PGE2 output and EP2 levels, intensifying inflammation while impairing the macrophages’ ability to consume neutrophils.

Andreasson’s team engineered mouse models in which the EP2 gene could be deleted specifically in tissue-resident macrophages, restoring the neutrophil-clearing process that PGE2 otherwise undermines.

The researchers compared young mice (six to eight months), normal old mice (23 to 25 months) and old mice with EP2 deleted earlier in life. Of 71 blood proteins altered in normal old mice, 59 stayed at youthful levels in the EP2-deleted old mice, many of which originated in the liver, which Andreasson said: “is the central organ that determines the body’s metabolic rate.”

Senescent neutrophils accumulated in the liver, spleen and bone marrow of normal old mice, while EP2-deleted old mice retained youthful counts. These mice were leaner and fitter, with less visceral fat and more muscle mass, and organ function matching young mice. Inflammation was reduced in the blood, liver, colon, heart, kidney and hippocampus. Speed, balance, grip strength and memory were largely preserved.

No currently approved drug can selectively block EP2. Within the mechanism NSAIDs block PGE2 production – which is how aspirin-like drugs reduce pain and swelling – but they also block other essential prostaglandins.

The research team also then treated 22-month-old mice for two months with an experimental EP2-inhibiting drug which reduced total and senescent neutrophil counts toward youthful levels and restored macrophages’ ability to engulf exhausted neutrophils in culture.

The team also examined a database of cellular activity across young, old and diseased human livers, finding the same pattern seen in mice, including neutrophil build-up and heightened EP2 activity, the first time this has been observed directly in human cells.

Targeting neutrophil clearance could offer real therapeutic benefit, Andreasson said, although a safe drug disabling EP2 without disrupting upstream processes such as PGE2 production would still need to be developed.

For further reading please visit: 10.1126/science.aea3075